1-(2-substituted-chromonyloxy)-2-hydroxy-3-(substituted-phenoxy)propanes

ABSTRACT

Definitions: in the following Formulae I, II and IV, R1 represents hydrogen, alkyl of 1 to 4 carbon atoms, or a nontoxic cation, while each of R2, R3, R4, R5, and R6 symbolizes hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, carboxy, carbalkoxy of 1 to 4 carbon atoms, trihalomethyl, halogen, nitro or cyano. Certain 1-(2-substituted-chromon-yloxy)-2-hydroxy-3(substituted-phenoxy)propanes (Formula I),   can be synthesized from intermediate bis-(substitutedphenoxy)propanes (Formula II),   by condensation with diethyl oxalate in the presence of sodium ethoxide followed by cyclization with a mixture of glacial acetic acid and concentrated sulfuric or a mixture of concentrated hydrochloric acid and a lower alcohol containing up to 4 carbon atoms. The bis-(substituted-phenoxy)propane intermediates (Formula II) are prepared by reacting a dihydroxyacetophenone (Formula III),   with a (substituted-phenyl)glycidyl ether (Formula IV),   in an organic solvent in the presence of a catalyst. The 1-(2-substituted-chromon-yloxy)-2-hydroxy-3-(substitutedphenoxy)propanes (Formula I) are useful in the treatment of allergic conditions in mammals. The bis-(substitutedphenoxy)propanes (Formula II) are useful as intermediates in the synthesis of the latter compounds. Methods of preparing compounds having Formulae I and II are described. Methods of treating allergic conditions in mammals utilizing compounds of Formula I are also disclosed.

United States Patent 1 Warren et al.

[ Aug. 12, 1975 i i i-( 2-SUBSTiTUTED-CHROMONYLOXY )-2- HYDROXY-ZS-(SUBSTITUTED- PHENOXYWROPANES [75] inventors: Brian Thomas Warren. lckenham;

John William Spieer. London. both of England (73] Assigned: Miles Laboratories. lne.. Elkhnrt.

' incl.

22\ Filed: Jami. ms

211 Appl.No.:320.600

[30] Foreign Application Priority Data Jan. 14. 1972 United Kingdom l9l2/72 {52] US. Cl. 260/3451; 260/345.5'. 424/283; 260/465 D; 260/473 S; 260/465 F; 260/514 .1; 260/Si4 K. 260/592 [5i] Int. Cl. C07d 311/02; C07d 3i 1/72 [58] Field of Search 260/3452. 345.5

(56] References Cited UNITED STATES PATENTS 3.5 l).652 7/1970 Fitzmuurice et al. 260/3452 3.673.2lli (i/l972 Cairns et nl 260/3451 3.792.063 2/l974 Cairns et nl ZOO/345.2 .l.li23.l(\$ 7/l974 Cairns cl ni 260/3453.

Primary Examiner.iohn M. Ford Allurncy. Agent. or Firm-Myron B. Sokolowski ii i no.1

can be synthesized from intermediate bis-(substitutedphenoxylpropnnes (Formula ll).

by condensation with diethyl oxalate in the presence of sodium ethoxide followed by cyclization with a mixture of glacial acetic acid and concentrated sulfuric or a mixture of concentrated hydrochloric acid and a lower alcohol containing up to 4 carbon atoms.

The bis-(substituted-phenoxy)propane intermediates (Formula II) are prepared by reacting a dihydroxyacetophenone (Formula Ill).

with a (substituted-phenyl)glycidyl ether (Formula I H ccfi Cl'i -O in an organic solvent in the presence of a catalyst. The;

l-( 2-substituted-chromon-yloxy )-2-hydroxy-3- (substituted-phenoxy)propanes (Formula I) are useful in the treatment of allergic conditions in mammals. The bis-(substituted-phenoxy)propanes (Formula ll) areiuseful as intennediates in the synthesis of the latter compounds. Methods of preparing compounds having Formulae i and ii are described. Methods of treating allergic conditions in mammals utilizing compounds of Formula I are also disclosed.

10 Claims. N0 Drawings 1 l-tZ-SUBS'IITUTED-CI-IROMONYLOXYl-2- HYDROXY-J-(SUBSTI'IU'IED- PHENOXY )PROPANES BACKGROUND OF THE INVENTION 2. Description of the Prior Art Khcllin. 4,9-dimethoxy-7-methyl-5H-furol3,2-g] [l] benzo-pyran-S-one (Formula V),

OCH

was first isolated, and its structure determined, by Sp'zith and Gruber (Ber. 7l: I06 [1938]). Khellin subsequently was utilized as a coronary vasodilator, as a bronchodilator, and as an agent for the treatment of colic.

Structural modifications of Khcllin led to the synthesis of -alkoxy substituted chromone-2-carboxylic acids (Formula VI).

wherein X can be a variety of substituted alkyl sidechains. Compounds of Formula VI are disclosed by Ellis and Wragg and by Fitzmaurice et al. in British Pat. Nos. l,049,289 (i966) and l,093,673 (i967) respectively. Such chromone derivatives exhibit biological activity in the treatment of allergic conditions, but such activity is of short duration (sec Cox et al., Adv. Drug Res. 5: I18 H9701). Because of the latter property, the S-alkoxy substituted chromone-Lcarboxylic acids had limited usefulness.

Clinically useful substituted bis-(2-carboxychromon-yloxy) derivatives were described by Fitzmaurice et al. in British Pat. No. l,l44,905 (1969), particularly disodium chromoglycate, or l,3-di(2- carboxy-4-oxochromon-5-yloxyl-2-hydroxy-propane disodium salt (Formula Vll) Disodiurn chromoglycate, known commercially as Intal, is used to treat allergic bronchial asthma. It produces, however, several untoward side effects.

SUMMARY OF THE INVENTION Definitions The following definitions apply throughout this Summary:

a. In any structural formula presented in the Summary, R represents hydrogen, alkyl of l to 4 carbon atoms, or nontoxic pharmaceutically acceptable cations.

b.-Also in any structural formula, R", R", R, R and R each represent hydrogen, alkyl of l to 4 carbon atoms, carboxy, carbalkoxy of l to 4 carbon atoms, trihalomethyl, halogen, nitro, cyano or alkoxy of l to 4 carbon atoms.

c. Carbon atom positions in ring moieties of the compounds disclosed are numbered clockwise; where the ring moiety is heteropolycyelic, the heteroatom is assigned the number one l and all other atoms in the ring are numbered sequentially in a clockwise manner, excluding atoms at ring juncturcs', to illustrate, chromone (benzo-y-pyrone) is numbered as follows:

d. The term Z-substituted-chromon-yloxy moiety l refers to the following chemical formula 6 O 2 R a i chromon-yloxy)-2-hydroxy-3-(substitutedphenoxy)propnnes (Formula I):

Designation of the carbon atoms in this structure folz s R R o R l 0 Cll 'Cli(OH)'CH -O 1 RO.,C

The 2-substituted-chromon-yloxy moiety is bonded to the remainder of Formula I at carbon atom positions 5. 6. 7. or 8. Bonding at positions 5. 6. or 7 is preferred. as represented by Formulae (la), (lb). and (lc):

lows the definition (c), supra. R' is defined in (a). su-

c. The term substituted-phenoxy moiety" refers to the structure .3 R o,c R 4 in the substituted-phenoxy moiety of Formula I. each of R. R". R. R and R is a substituent as defined in the Definitions above. it is preferred that: (:1) either all substituents R through R". inclusive. are hydrogen; or (b) only 3 of substituents R through R. inclusive. are hydrogen. while the other two substituents are other than hydrogen. Among the preferred embodiments of the substituted-phenoxy moiety of Formula l are the following:

phenoxy p-bromophenoxy p-ehlorophenoxy p-fluorophenoxy p-methoxyphenoxy m-cresyloxy o-cresyloxy p-(t-butyl)phenoxy 2.6-dimethylphenoxy 2.5-dimethylphenoxy p-ethylphenoxy o-( n-propyl )phenoxy m-trifluoromethylphenoxy p-curhethoxyphenoxy p-cyanophenoxy p-nitrophenoxy 2.4-dichlorophenoxy 3-methoxy-4-cyanophenoxy Il-methoxy-4-carboxyphenoxy 3-methoxy-4-cztrhethoxyphenoxy Preferred embodiments of Formula I include the following compounds:

l-( Z-carboxychromon-S-yloxy)-2-hydroxy-3- phenoxypropane. the ethyl ester and the sodium salt thereof (Examples 2.3.4);

I-( 2-carboxychromon-5-yloxy)-2-hydroxy-3-pbromophenoxypropane. the ethyl ester. and the sodium salt thereof (Examples 6. 7. 8);

l-( 2-carboxychromon-S-yloxy 2-hydroxy-3-pchlorophenoxypropane. and the ethyl ester thereof (Examples l0 and ii);

l-(2-carboxychromon-5-yloxy)-2-hydroxy-3-pmethoxyphenoxypropane. the ethyl ester. and the sodium salt thereof (Examples l3. l4.

l-( Z-carboxychromon-S-yloxy )-2-hydroxy-3-ocresyloxypropane. the ethyl ester and the sodium salt thereof(Examples l7. l8. l9);

l-( 2-earboxychromon-S-yloxy)-2-hydroxy-3-p-( tbutyl) phenoxypropane. the ethyl ester. and the sodium salt thereof (Examples 21. 22. 23);

l-( Z-carboxychromon-S-yloxy )-2-hydroxy-3-( 2.6- dimethylphenoxy)propane and the ethyl ester thereof (Examples 25 and 26);

l-( 2-earboxychromon-S-yloxy)-2-hydroxy-3-mcresyloxypropaue and the ethyl ester thereof (Exampics 28 and 29)".

l-(Z-earboxychromon-S-yloxyl-2-hydroxy-3-p-ethylphenoxypropane sodium salt and ethyl ester (Examples 3i and 32);

l-(2-carboxychromon-5-yloxy)-2-hydroxy-3-pcyanophenoxypropane sodium salt and ethyl ester (Examples 34 and 35).

(ill

l-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-nitrophenoxypropane sodium salt and ethyl ester (Examples 37 and 38);

l-(2-carboxychromon-7-yloxy)-2-hydroxy-3- phenoxypropane and the sodium salt thereof (Examples 40 and 41 l-(2-carboxychromon-5-yloxy)-2-hydroxy-3 pethoxyphenoxypropane and the sodium salt thereof (Examples 42 and 44);

l-(2-carboxychromon-5-yloxy)-2-hydroxy-3-(2.5- dimethylphenoxy)propane sodium salt and ethyl ester (Examples 46 andfll h l-(Z-earboxychromon-S-yloxy)-2-hydroxy-3-o-(npropyl)phenoxypropane sodium salt and ethyl ester (Examples 49 and 50);

l-(2-carboxychromon-7-yloxy)-2-hydroxy-3-pcyanophenoxypropane sodium salt and ethyl ester (Examples 52 and 53);

l-(2-carboxychromon-6-yloxy)-2-hydroxy-3-pcyanophenoxypropane sodium salt and ethyl ester (Ex' amples 55 and 56);

l-(2-carboxychromon-5-yloxy)-2-hydroxy-3-mtrifluoromethylphenoxypropane sodium salt and ethyl ester (Examples 58 and 59);

l-(2-carboxyclu'outon-5-yloxy)-2-hydroxy-3-(2.4- dichlorophenoxy)propane sodium salt and ethyl ester (Examples 6] and 62);

l-( 2-carboxychromon-5-yloxy )-2-hydroxy-p-fluorophenoxypropane sodium salt and ethyl ester (Examples 64 and 5 l-( 2-carboxychromon-S-yloxy )-2-hydroxy-3-( 3- methoxy-4-cyanophenoxy)propane sodium salt and ethyl ester (Examples 67 and (18);

l-(2-earboxychromon-5yloxy)-2-hydroxy-3-(3- methoxy-4-carbethoxyphenoxy)propane sodium salt and ethyl ester; and

l-(2-carboxychromon-5-yloxy)-2-hydroxy-3-(3- methoxy-4-carboxyphenoxy)propane. disodium and ethyl ester.

salt

Dose forms of compounds of Formula (I) can be prcpared in compositions by the addition of pharmaceutically acceptable carriers generally used in the formulation of pharmaceutical compositions. Such compositions can be prepared in the solid or liquid state by methods known in the art for administration by inhalation, ingestion. intravenous or parenteral injection. and by other means. For the treatment of asthma. the compositions may be in a form suitable for administration by inhalation. Thus the compositions may comprise a suspension or solution of the l-( 2-substitutedchromon-yloxy)-2-hydroxy-3-(substitutedphenoxy)propane in water or in a suitable alcohol for administration as an aerosol by means of a conventional nebuliser. Alternatively. the compositions may comprise a suspension or solution of the active ingredient in a conventional liquefied propellant to be administered as an aerosol from a pressurized container. The compositions may also comprise the solid active ingredient in a solid diluent for administration from a powder inhalation device. Other routes of administration. e.g. sublingual, oral or buccal tablets, rectal suppositories or intravenous injection or infusion may also be used.

The compositions may also contain. in addition to the compound of general Fonnula i. other active ingrediform of Formula I (i.e. R is lower alkyl of] to 4 carbon atoms). Nontoxic, pharmaceutically acceptable salts of Formula I (i.e. R is a nontoxic cation) can be prepared from the acid form by reacting the latter with a carbonate solution having the desired cationic species or from the ester forms by saponifieation. in the above process. Formula II has the following preferred embodiments:

---C'l,Cli(Oii}'Cii 3 (I18) an R R '-CH 'CH(OH)-CH "C 6 R ii C R ii C "CH -CH(OH)'CH O H0 6 2 ents, for instance other bronchodilators. These additional bronchodilators can include those of the B-adrenergic type, such as isoor orci-prcnaline. salbutamol. or a pharmaceuticaliy acceptable salt thereof. The compositions may contain 0.1 to 10% by weight of the compound of Formula i. ll salbutamoi or isoor orci-prenaline sulphate is used. it is suitably present in a concentration of 0.1 to 5% by weight.

Compounds of Formula I can be prepared from bis- (substituted-phenoxy)propanes (Formula ll),

by condensation with dicthyl oxalate in the presence of 40 Compounds having Formula ii are useful in the prep- (ill with a tuabstitatcd-phcnyl)glycidyl cthcr (Formula Vii aallum cthoidde. followed by cycllmtloa with a mixlure of glacial acetic and concentrated sulfuric acids to obtain the acid form of Formula i (Le. R' is hydrogen H2C (;H H2 R U V) or a mixture oi conccntratcd hydrochloric acid and a lowcr alcohol oil to 4 carbon atoms to obtain the ester R R in an appropriate organic solvent in the presence of a catalyst.

In the synthesis described above the following are preferred embodiments:

a. The dihydrtixyaeetophenone (Formula III) is 2,6- dihydroxyaeetophenone. 2,4- dihydroxyaeetophenone or 2.5-

dibydrtixyaeetophenone.

h. The organic solvent is 2-ethoxyethanol.

e. The eatalyxt ix benxyltrlntethylamntonium hydroxlde. d. The reaction ls performed under rellux.

e. The following are preferred substituted-phenyl moieties in Formula IV phenyl p-bromophenyl p-ehlorophenyl p-fluorophenyl p-methylphenyl m-eresyl o-eresyl p-( t-butyl )phenyl 2.6-dimethylphenyl 2.5-dimethylphenyl p-ethylphenyl o-( n-propyl )phenyl m-trifluoromethylphenyl p-earhethoxyphenyl p-earboxyphenyl p-eyanophenyl 2,4'diehlorophenyl 3-methoxy-4-earbethoxyphenyl 3-methoxy-4-cyanophenyl 3-methoxy-4-carboxyphenyl Preferred embodiments of Formula lla include:

I-( 2-aeetyl-3-hydroxyphenoxy )-2-hydroxy-3- phenoxypropanc (Example I; Intermediate to Examples 2,3. and 4);

l-( 2-acetyl-3-hydroxyphenoxy )-2-hydroxy-p-bromophenoxypropane (Example 5; Intermediate to Examples 6. 7 and 8);

l-( 2-aeetyl-S-hydroxyphenoxy )-2-hydroxy-p-,ehlorophenoxypropanc (Example 9; Intermediate to Exam- 10 l-( Z-aeetyl-3-hydroxyphenoxy )-2-hydroxy-p-ethylphenoxypropane (Example Intermediate to Examples 3i and 32);

l-( 2-aeetyl-T -hydroxyphentixy )-2-hydroxy-3-p- 5 eyanophenoxypropane (Example 33; Intermediate to Examples 34 and 35);

l-(2-aeetyl-B-bydroxyphcnoxy)-2-hydroxy-3-pearbetboxy-phenoxypropnne (Example 42; Intermedim ate to Examples 43 and 44);

l-(2-aeetyl-3-hydroxyphenoxy)-2-hydroxy-3-(2.5- dlmethyl-phenoxy)propune (Example 45r Intermediate to Examplex 46 and 47);

l-( 2-aeetyl-Il-hydroxyphenoxy )-2-hydroxy-3-( 2-n- 5 propyl-phenoxy)propane (Example 48; Intermediate to Examples 49 and 50);

l-( 2-aeetyl-3-hydroxyphenoxy )-2-hydroxy-3-( mtrifluoro-methylphenoxy)propane (Example 57; Inter 2o mediate to Examples 58 and 59);

l-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-Il-(2.4- diehloro-phenoxy)propane (Example 60; Intermediate to Examples 6l and 62);-

l-( 2-aeetyl-B-hydroxyphenoxy )-2-hydroxy-3-p- 25 fluorophenoxy-propane (Example 63; Intermediate to Examples 64 and 65);

l-( 2-acetyl-3-hydroxyphenoxy )-2-hyd roxy-3-( 3- methoxy-4-eyanophenoxy)propane (Example 66, In-

.10 termediate to Examples 67 and 68);

l-( 2-aeetyl-B-hydroxyphenoxy )-2-hydroxy-3-( 3- methoxy-4-earboxyphenoxy )propane; and

l-( Z-ueetyl-B-hydroxyphenoxy )-2-hydroxy-3-( 3- methoxy-4-carbethoxyphenoxy )propane.

5 Preferred embodiments of Formula Ilb include:

I-( 3-aeetvl-4-hydroxyphenoxy )-2-hydroxy-3- phenoxypropanc (Example 39; Intermediate to Examples 40 and 41 and l-( 3-acetyl-4-hydroxyphen0xy )-2-hydroxy-3-pcyanophenoxy-propane (Example SI: Intermediate to Examples 52 and 53).

Preferred embodiments of Formula llc include:

I-( 3-hydroxy-4-acetylphenoxy )-2-hydroxy-3- 45 phenoxypropane (Example 54; Intermediate to Examples S5 and 56).

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE I l-( Z-Acetyl-3-hydroxyphcnoxy )-2-Hydroxy-3- Phenoxypropanc. A solution of 2.6-dihydroxyacetophenone (15.2 g).

phenylglycidyl ether (l5.0 g) and benzyltrimethylammonium hydroxide (5 drops of a 40% solution) in 2- ethoxyethanol ml) was heated under reflux for 48 hours. The solvent was removed under reduced pres sure and the resulting solid was washed with ether. Re crystallization from aqueous ethanol gave I-(ZaeetyL 3-hydroxyphenoxy )-2-hydroxy-3-phenoxypropane.

5 l).() g. as pale lemon needles. mp lt)().5-lt)l.SC.

Analyxix: Found: C. 67.4%; H. 6.0%; C H O re quires C. 67.6%. H, 6.0%.

EXAMPLE 2 l-( Z-Carboxychromon-S-yloxy )-2-Hydroxy-3- Phenoxypropane.

late (30 ml) was added to a suspension of sodium ethoxide, prepared from sodium (6.0 g) and ethanol (60 ml). in benzene (100 ml). The mixture was heated under reflux for L5 hours, cooled and poured into ether. The precipitated yellow solid was collected, washed with ether and dried. The solid was then added to a mixture of glacial acetic acid (80 ml) and concentrated hydrochloric acid (30 ml) and heated under reflux for l hour. After cooling, the reaction mixture was poured with stirring into cold water lL). The precipitated gum was washed with water by decantation and solidified by trituration with acetic acid. Recrystallization from acetic acid gave l-(2-carboxychromon-5- yloxy)-2-hydroxy-3-phenoxypropane (7.0 g) as a white powder, m.p. 88-90C.

Analysis: Found: C. 59.4%; H, 4.9%; C,,,H,.,O,. 3/,H,O requires C, 59.5%; H, 4.9%.

EXAMPLE 3 l-( Z-Carbethoxychromon-S-yloxy )-2-Hydroxy-3- Phenoxypropane.

EXAMPLE 4 l-( 2-Carboxychromon-5-yloxy)-2-Hydroxy-3- Phenoxypropane Sodium Salt.

A solution of sodium hydroxide (0.6 g) in ethanol (I ml) was added to l-(2-carbethoxychromon-5- yloxy)-2-hydroxy-3-phenoxy-prupune (5.7 g) and the mixture was heated under reflux on a water bath for l hour. The solid that separated was filtered off and recrystallized t'rom water (charcoal) to give l-(2- carboxyehromon-S-yloxy)-2-hydroxy-3- phenoxypropane sodium salt, (2.3 g), solid, mp. 22l-223C.

a slightly pink Analysls: Found: C, 60.42%, H, 4.6l%; C H O Na requires C, 60.3%; H, 3.98%.

EXAMPLE 5 l-(2-Acetyl-S-hydroxyphenoxy)-2-Hydroxy-3-p- Bromophenoxypropane.

A solution of 2,b-dihydroxyacetophenone (l5.2 g) and p-bromophenylglycidyl ether (22.9 g) in 2- ethoxyethanol (75 ml) containing benzyltrimethylammonium hydroxide solution (l0 drops: 40%) was heated under reflux for 72 hours. The UlVCnt was removed by distiilation under reduced pressure and the residual viscous orange oil was allowed to stand overnight during which time crystallization commenced. The residue was triturated with diethyl ether and the solid collected. l-(2-acetyl-3-hydroxy-phenoxy)-2- hydroxy-3-p-bromophenoxypropane, was obtained as a pale yellow solid, l6.4 g; m.p. l0l.5-l03C.

Analysis: Found: C, 53.8%; H, 4.5%; Br, 2l.l;l.; C H BrQ, requires C, 53.6%; H, 4.5%; Br, 2i 6%.

EXAMPLE 6 l-( 2-Curbethoxychromon-S-yloxy )-2-Hydroxy-3-p- Bromophenoxypropanc.

A mixture of l-(Z-acetyl-3-hydroxyphenoxy)-2- hydroxy-3-p-bromophenoxypropane (lS.2 g) and diethyl oxalate l5 ml) was added to a suspension of sodium ethoxide (prepared from 3.0 g sodium) in absolute ether. The mixture was heated under reflux for L5 hours and then poured onto ice l00 g). After acidification with a solution of acetic acid (l2 mi) in water ml), the ether layer was separated and the aqueous layer was extracted with ether (3 X 25 ml). The combined ether solutions were evaporated and the residue was dissolved in a mixture of acetic acid (80 ml) and hydrochloric acid (30 ml) and heated under reflux for l hour. Recrystallization from acetic yielded crude l- (2-carboxychromon-5-yloxy)-2-hydroxy-3-p-bromophenoxypropane, i4.7 g), as a white solid, mp. l88-l90, which was converted to the ethyl ester employing absolute ethyl alcohol and concentrated sulphuric acid as catalyst. l-( 2-carbethoxychromon-5- yloxy)-2-hydroxy-3-p-bromophenoxypropane was obtained as white crystals, m.p. 7980 after recrystallization from aqueous dioxane.

Analysis: Found: C, 54.05%; H, 4.32%; Br, 17.06%; C H BrO requires C, 54.4%; H, 4.1%. Br, 17.25%.

EXAMPLE 7 l-( 2-Carboxychromon-5-yloxy-2-Hydroxy-3-p-Bromophenoxypropane.

A solution of sodium hydroxide (0.6, g) in ethanol (I00 ml) was added to l-(2-earbethoxychromon-5- yloxy)-2-hydroxy-3-p-bromo-phenoxypropane (6.6 g) and the mixture was heated under reflux for l hour. The resulting sodium salt was flltered, dissolved in the minimum volume of hot water and poured into a solution of acetic acid (lOO ml: 2N). The solution was cooled, the precipitated acid was collected, washed with cold water and dried. Recrystallization from dilute acetic acid gave l-(2-carboxychromon-5-yloxy)-2- hydroxy-3-p-bromophenoxypropane (6.05 g) as white needles, mp. l92-l94C.

Analysis: Found: C, 49.98%; H, 3.85%; Br, l8.03%: C,,,H BrO,.H,O requires C, 50.3%; H, 3.75%, Br. l7.67%.

EXAMPLE 8 l-(2-Carboxychromon-5-yloxy)-2-Hydroxy-3-p- Bromophenoxypropane Sodium Salt.

A solution of sodium carbonate (0. IN, ml) was added to l-(2-earboxychromon-5-yloxy)-2-hydroxy-3- p-bromophenoxypropane (4.35 g). The suspension was heated on a water bath until the acid had dissolved completely and allowed to cool. The iridescent solid that separated was collected by centrifugation and washed with water (I ml). The product was finally freeze-dried to give I-(2-carboxychromon-5-yloxy)-2- hydroxy-3-bromophenoxypropane sodium salt (3.3 g),

m.p. 254-256C.

Analysis: Found: C, 49,6696, H, 3.54%; Br, l7.30% C,,,H,.BrO,Na requires C,49.9%; H, 3.32%; Br, l7.5%.

EXAMPLE 9 i-( 2-Acetyl-3-hydroxyphenoxy )-2-Hydroxy-3-p- Chlorophenoxy-propane.

EXAMPLE I0 I-( 2-Carbethoxychromon-S-yloxy )-2-Hydroxy-3-p Chlorophenoxypropane.

A mixture of l-(2-acetyl-B-hydroxyphenoxy)-2- hydroxy-3p-chlorophenoxypropane (l3.5 g) and diethyl oxalate ml) was added to a suspension of alcohol-i'ree sodium ethoxide (prepared from sodium 3 g) in absolute ether (200 ml). The mixture was heated under reflux for 1.5 hours during which time a yellow solid separated. The reaction mixture was poured onto ice (100 g) and acidified with a solution of acetic acid (l2 ml) in water (80 ml). The ether layer was separated and the aqueous layer extracted with ether (3 X 25 ml). The ether layer was combined with the ether extracts and the solvent was evaporated. Acetic acid (80 ml) and hydrochloric acid (30 ml) were added to the residue and the resulting solution was heated under reflux for I hour. On pouring into water a beige gum was precipitated which soon solidit'ed and was filtered. Recrystallization from acetic acid gave crude l-(2- carboxychromon-S-yloxy)-2-hydroxy-3-p-chlorophenoxypropane (12.0 g), as a white solid, mp. l9ll93. The impure acid (10 g) was heated under reflux for 5 hours with ethanol (I00 ml) and concentrated sulphuric acid I0 drops). The solvent was then removed on a rotary evaporator; the residual oil was dissolved in chloroform and washed successively with sodium bicarbonate solution and water. The solvent was removed and a small volume of ether was added to the residual oil which slowly crystallized to give a white solid (8.4 g), m.p. 98IO0. Recrystallization from aqueous ethanol gave l (2-carboxychromon-5-yloxy)- Z-hydrnxy-3-p-chloro-phenoxypropane (6.6 g) as white l'iuffy needles, mp. 98-l00C.

Analyst's: Found: Cl, 8.46%; C- H ClO requires Cl, 8.48%.

A white solid that separated while washing with sodium bicarbonate solution was filtered, washed with cold water and dried to give I-(Z-carboxychromon-S- yloxy)-2-hydroxy-3-p-chlorophenoxypropane sodium salt, (l.6 g). mp. 242C.

Analysis: Found: C, 54,04%; H, 3,76%; Cl, 8.82%; C ,H ClO .l/ H O requires C, 54.1%; H, 3.8%; Cl. 8.43%.

EXAMPLE I l l-(2-Cttrlxixyeliromon-tl-yloxy )d-ilydroxy-S-p- Chlorophenoxypropune.

A solution of sodium hydroxide (0.6 g) in ethanol was added to I-(2-carbethoxychromon-5-yloxy)-2- hydroxy-3-p-chlorophenoxypropane (6.28 g) and the mixture was heated under reflux for 1 hour. The resulting sodium salt was filtered, dissolved in the minimum volume of hot water and poured into a solution of acetic acid I00 ml, 2N). The solution was cooled, the precipitated acid was filtered, washed with cold water and dried. Recrystallization from dilute acetic acid gave l-(2-carboxychromon-5-yloxy)-2-hydroxy-3-pchlorophenoxypropane (6.0 g) as white needles, mp.

l93-l95C.

Analysis: Found: C, 55.22%; H, 4.56%; Cl, 8.56%; CmHmClO-yHgo requires C, H, Cl, 8.68%.

EXAMPLE 12 l-( 2-Acetyl-3-hydroxyphenoxy-2-Hydroxy-3-p- Methoxyphcnoxy-propane.

A solution of 2,6-dihydroxyacetophenone (152g) and p-methoxyphenylglycidyl ether (I8.0g) in 2- ethoxyethanol ml) containing benzyltrimethylammonium hydroxide solution (5 drops: 40%) was heated under reflux for 48 hours. The solvent was then removed under reduced pressure and the residual viscous orange oil was allowed to stand overnight during which time crystallization occured. The solid was triturated with ether, filtered and washed with a little ether to give I-( 2-acetyl-B-hydroxyphenoxy )-2-hydroxy-3-pmethoxyphcnoxypropane (18.65 g) as a pale yellow solid, mp. l00-IOI.5C.

Analysis: Found: C, 64.9%; H, 5.95%, C H O requires C, 65.l%; H, 6.0%.

EXAMPLE I3 I-( 2-Carboxychromon-5-yloxy )-2-Hydroxy-3p- Methoxyphenoxypropane.

due was dissolved in a mixture of acetic acid ml) and hydrochloric acid (30 ml) and heated under reflux for 1 hour. On pouring into water (i L) an off white solid was precipitated which was collected and recrystallized from acetic acid to give l-( 2-carboxy chromon- 5-yloxy)-2-hydroxy-3-p-methoxyphenoxypropane (12.0 g) as a white solid. mp. i25-l 26C.

Analysis: Found: C. 59.12%; H, 4.94%; C-, H,..O,.H O requires C. 59.4%; H. 4.94%.

EXAMPLE l4 i-( 2-Carbethoxyehromon-S-yloxy )-2-Hydroxy-3-p- Methoxyphenoxypropane.

A mixture of l-(2-eurhoxyehrolnon-S-yioxy)-2- hydroxy-3-p-methoxy-phenoxyprepune U00 3). ethyl alcohol (Sml). benzene l00 ml) and concentrated sulphuric acid (5drops) was heated under a Dean and Stark phase separator for hours. The cooled solution was washed with saturated sodium bicarbonate solution and then with water. Removal of the benzene under reduced pressure afforded a solid which was recrystallized from aqueous dioxane to give l-(2- carbethoxychromon-S-yioxy)-2-hydroxy-3-p-methoxyphenoxy-propanc. m.p. i-l3.5C as white needles.

Analyst's. Found: C H, CggHggOn requires C. 63.7%; H. 5.3l%.

EXAMPLE l5 l-( 2-Carboxychromon-5-yloxy )-2-Hydroxy-3-p- Methoxyphenoxypropane Sodium Salt.

A solution of sodium hydroxide (0.6 g) in ethyl alcohol (lOO ml) was added to l-(2-carbethoxychromon-5- yloxy)-2-hydroxy-3-p-methoxyphenoxypropane (6.2 g) and the mixture was heated under reflux for 1 hour. The resulting solid was filtered and recrystallized from water to yield hydroxy-3-p-methoxyphenoxypropane sodium salt (5 g) as a light beige solid mp. 22l-223C.

Analysis: Found: C. 56.56%; H. 4.42%; C H O Na H 0 requires C. 56.3%; H. 4.7%.

EXAMPLE l6 l-( 2-Carboxychromon-5-yloxy )-2-Hydroxy-3-o- Cresyloxypropane A solution of 2.6-dihydroxyacetophenone (15.2 g) and o-eresyl-glycidyl ether l6.4 g) in 2-ethoxyethanol (75 ml) containing benzyltrimethylammonium hydroxide solution (l0 drops; was heated under reflux for 48 hours. Following removal of the 2-ethoxyethanol under reduced pressure. the resulting solid was washed with ether to give l-(2-acetyi-3-hydroxyphenoxy)-2- hydroxy-3o-cresyloxypropane (l9.2 g) as a cream solid, mp. l0l-i02.5C.

Analysis: Found: C. 68.l%; H. 6.3%; CuJHZOOb requires C. 68.3%; H. 6.4%.

EXAMPLE l7 l-( 2-Carboxychromon-5-yloxy )-2-Hydroxy-3-o- Cresyloxypropane.

A solution of l-(2-acetyl-3-hydroxyphenoxy)-2- hydroxy-3-o-cresyloxypropane (l8.96 g) in diethyi oxalate (22.5 ml) was added to a suspension of sodium ethoxide. prepared from sodium (4.5 g) and ethyl alcohol (4.5 ml). in benzene (150 ml). The mixture was heated under reflux for L5 hours. cooled. and filtered nl'ter pouring into ether (l50 ml). The residual solid was washed with ether and dried. and then added to n l-(2-carboxychromon-5-yloxy)-2- EXAMPLE i8 l-( 2-Carbethoxychromon-S-yloxy )-2-Hydroxy-3-o- Cresyloxypropane.

A mixture of l-(2-carboxychromon-5-yloxy)-2- hydroxy-3-o-crcsyioxypropane (l0.0 g). ethyl alcohol (5 ml). benzene (100 ml) and concentrated sulphuric acid (5 drops) were heated together under a Dean and .Stark trap for 18 hours. After cooling. the solution was washed successively with sodium bicarbonate solution and water. Removal of the benzene afforded a viscous oil nucleated with crystals. Recrystallization of the crude product from aqueous dioxane gave l-(2- carbethoxychromon-5-yloxy)-2-hydroxy-3-ocresyioxypropane (8.75 g). m.p. 76C.

Analysis: Found: C. 63.75%; H. 6.00%; C,,H ,O,H,O

requires C. 63.4%; H. 5.77%.

EXAMPLE l9 l-(2-Carboxychromon-5-yloxy)-2-Hydroxy-3-o- Cresyloxypropane Sodium Salt.

A solution of sodium hydroxide (0.8 g) in ethyl alcohol ml) was added to l-(2-carbethoxyehromon-5- yloxy )-2-hydroxy-3-o-cresyloxypropane (7.96 g) and the mixture heated under reflux for 1 hour. The resulting solid was filtering and washed with a small volume of cold water to give l-( 2-carboxychromon-5-yloxy)-2- hydroxy-3-o-cresyloxypropane sodium salt (3.8 g). m.p. 228-230C.

Analysis: Found: C. 60.23%; H. 4.22%; C H O Na requires C. 61.2%; H. 4.33%.

EXAMPLE 20 l-(2-Acetyl-3-hydroxyphenoxy)-2 Hydroxy-3-p-t- Butylphenoxypropane.

A solution of 2.6-dihydroxyacetophenone (15.2 g). p-t-butylphenylglycidyl ether (20.6 g) and benzyltrimethylammonium hydroxide (5 drops of a 40% solution) in a 2-ethoxyethanoi (75 ml) was heated under reflux for 48 hours. The solvent was removed under reduced pressure giving l-(2-aeetyl-3-hydroxyphenoxy)-2 hydroxy-3-p-t-butylphenoxypropane (38.85 g) as a viscous orange oil.

EXAMPLE 2i l-( 2-Carboxychromon-5-yloxy )-2-Hydroxy- 3-p-t- Butylphenoxypropane.

A solution of l-(2-acetyl-3-hydroxyphenoxy)-2- hydroxy-3-p-t-butylphenoxypropnne l4.4 g) in diethyl oxalate (15 ml) was added to a suspension of sodium ethoxide. prepared from sodium (3.0 g) and ethanol (30 ml). in ether (200 mi). The mixture was heated under reflux for L5 hours. and the brown-coloured residue was poured onto ice (-l g). After acidification with a solution of acetic acid l2-ml) in water (80 ml). the ether layer was separated. and the aqueous solution extracted with ether (3 x25 ml). The solvent was then removed from the combined ethereal layer and ethereal extracts. The residue was dissolved in a mixture of acetic acid (80 ml) and hydrochloric acid (30 ml) and heated under reflux for l hour. On pouring into water (i L) l-(Z-carboxychromon-S-yloxy)-3p-t-butylphenoxypropane. 10.7 g. was obtained as a beige gum.

EXAMPLE 22 l Z-Carbethoxychromon-S-yloxy)-2-Hydroxy-3-p-t- Butylphenoxypropane.

l-( Z-carboxychromon-S-yloxy )-2-hydroxy-3-p-tbutylphenoxypropane i0.7 g). benzene (100 ml). ethanol (5 ml) and sulphuric acid drops) were heated under reflux in a Dean and Stark separator until no more water passed over (about 6 hours). Afier cooling.

the solution was washed with saturated sodium biear- EXAMPLE 23 l-( Z-Carboxychromon-S-yloxy )-2-Hydroxy-3-p-t- Butylphenoxypropane Sodium Salt.

A solution of sodium hydroxide (0.4 g) in ethanol (lOO ml. 96%) was added to l(2-carbethoxychromon- 5-yloxy)-2-hydroxy-3-p-t-butylphenoxypropane (4.40 g) and the mixture warmed gently under reflux for 10 minutes. The cream solid was filtered off. washed with a little ethanol. and dried. it was then dissolved in water. charcoaled. filtered. and poured into dilute acetic acid. The sticky solid was filtered ofl'. dissolved in acetone. and the acetone concentrated to give a yellow solid (3.5 g) m.p. 90. This solid dissolved in sodium carbonate solution (0.1N. 85 ml) and the solution filtered and freeze-dried to give the sodium salt (3.9 g) as an off-white solid mp. 230-232.

Analysis: Found: C. 57.42%; H. 5.55% C H mNa. 2.5H,0 requires C. 57.6%; H.5.88

EXAMPLE 24 l-( 2-Acetyl-3-hydroxyphenoxy)-2 Hydroxy-3-( 2.6- dimethylphenoxy)propanc. propane.

18 ous ethanol to give pale yellow prisms. m.p. 88-90C. Analysis: Found: C. 68.83%; H. 6.62% C H O requires C. 69.07%; H. 6.71%.

EXAMPI 25 i-(Z-Carbethoxychromon-S-yloxy)-2-Hydroxy-3-( 2.6- dimethylphenoxy )propane.

A solution of l-(2-acetyl-3-hydroxyphenoxy)-2- hydroxy-H2.6-diaietliyiplieauxy) propane (l2.7 g) in diethyl oxalate (l5 ml) was added to a suspension of sodium ethoxide. prepared from sodium (3.0 g) and ethanol (30 ml). in ether (200 ml). The mixture was heated under reflux for L5 hours. and the resulting cherry-red solution poured onto ice iOO 8). and acidified with a solution of acetic acid l2 ml) in water ml). The ether layer was separated, and the aqueous layer extracted with ether (3 X 25 ml). adding the extracts to the organic layer. The solvent was then removed and the residue dissolved in absolute ethanol (l00 ml) to which hydrochloric acid (5 drops) was added. The yellow solution was heated under reflux for 0.5 hours and the solvent removed to give l-(2- carbethoxychromon-S-yloxy)-2-hydroxy-3-(2.6- dimethyl) -phenoxypropane as a viscous yellow oil (15.9 g).

EXAMPLE 26 l-( 2-Carboxychromon-5-yloxy)-2-Hydroxy-3-( 2.6- dimethylphenoxy)propane Sodium Salt.

EXAMPLE 27 l-( 2-Acetyl-3-hydroxyphenoxy )-2-Hydroxy-3-m- Cresyloxypropane.

A solution of 2.6-dihydroxyacetophenone (l5.2 g). m-cresylglycidyl ether 16.4 g) and benzyltrimethylammonium hydroxide (l0 drops of a 40% solution) in a 2-ethoxyethanol (75 ml) was heated under reflux for 48 hours. The solvent was then removed under reduced pressure to give l-(Z-acetyl-3-hydroxyphenoxy)-2- hydroxy -3-m-cresyloxypropane (3L5 g) as a viscous amber oil.

EXAMPLE 28 i-( Z-Carbcthoxychromon-S-yloxy )-2-Hydroxy-3-m- Cresyloxypropane.

A solution of l-(2-acetyl-Zl-hydroxyphenoxy)0 hydroxy-3art-cresylosypropane (25.3 g) in dlcthyl oxalate (30 ml) was added to a suspension of sodium ethoxide. prepared from sodium (6.0 g) and ethanol (60 ml in dry ether (400 ml). The mixture was heated under reflux for L5 hours; the brown residue was poured onto ice (200 g) and acidified with a solution of acetic acid (24 ml) in water mi). The ether wcre filtered off. and washed with tho and the aqeuous layer extracted with ether (3 X 50 ml).

adding the extracts to the organic layer. The solvent was then removed and the residue dissolved in absolute ethanol (200 ml). to which hydrochloric acid l drops) was added. The solution was heated under reflux for 30 minutes and the solvent removed to give a viscous brown oil. which solidified on standing. The oily crystals were filtered off and after recrystallization from aqueous ethanol gave l-(2-carbethoxy-chromon- -yloxy)-2 -hydroxy-3-m cresyloxypropane (8.2 g) as a white solid. m.p. 72'-74.

Analysis: Found: C. 62.55%; H. 5.80%; C,,H-.,O,.l.5H,O requires C. 62.2%; H. 5.92%.

EXAMPLE 29 l Z-Carboxychromon-S-yloxy )-2-Hydroxy-3-m- Cresyloxypropane Sodium Salt.

EXAMPLE 30 l 2-Acetyl-3-hydroxyphenoxy )-2-Hydroxy-3-p-Ethylphenoxypropane.

A solution of 2.6-dihydroxyacetophenone (l5.2 g). p-ethylphenyl ether (l7.8 g) and benzyltrimethylammonium hydroxide (5 drops of a 40% solution) was heated under reflux for 3 days. The solvent was removed under reduced pressure affording l-(2-acetyl-3- hydroxyphenoxy)-2-hydroxy-3-p-ethylphenoxypropane. 33.0 g. as a cherry-red oil.

EXAMPLE 3i l 2'Carbethoxychromon-S-yloxy )-2-Hydroxy-3-p- Ethylphenoxypropane.

A solution of l-(2-acetyl-3-hydroxyphenoxy)-2- hydroxy-3-p-ethylphenoxypropane (25.6 g) in diethyl oxalate (30 ml) was added to a suspension os sodium ethoxide. prepared from sodium (6.0 g) and ethanol (60 ml). in dry ether (400 ml). The mixture was heated under reflux for L5 hours and the greenish-brown residue was poured onto ice (200 g) and acidified with a solution of acetic acid (24 ml) in water (160 ml). The ether layer was separated after the addition of a further quantity of water (200 ml). and the aqueous layer was 5 extracted with ether (3 X ml). adding the extracts to the organic layer. The solvent was then removed and the residue dissolved in absolute ethanol (200 ml) to which hydrochloric acid l0 drops) was added. The so lution was heated under reflux for 1 hour and the solvent was then removed to give a brownish oil from which crystals separated on standing overnight. These minlmum volume of ether to afl'ord l-(2-carbethoxy-chromon-5- yloxy)-2-hydroxy-3-p-ethylphenoxypropune (l5.7 g) as a white solid. mp. 80-85. A portion was recrystallized from aqueous ethanol to give white flakes. m.p. 84-86.

20 Analysis: Found: C. 64.58%; H. 6.19% C -.H.O H 0 requires C. 64.l7%; H. 6.09%.

EXAMPLE 32 l-( 2-Carboxychromon-5-yloxy )-2-Hydroxy-3-p' Ethylphenoxy-pro'pane Sodium Salt.

A solution of sodium hydroxide (l'.2 g) in ethanol ml. 96 70) was added to a solution of H2- carbethoxychromon- 5-yloxy )-2-hydroxy-3-p-ethylphenoxypropanc (12.4 g) in ethanol (lOO ml. 96%) at room temperature. The mixture was then heated under reflux on a water bath for 30 minutes. allowed to cool. and the solid filtered off. washed with ethanol. and dried. it was then recrystallized from water. and finally redissolved in water. filtered and freeze-dried to give the sodium salt (5.9 g) as a silvery-white solid. mp. 235.

Analysis: Found: C. 62.07%; H. 4.94%; C,.H. 0,Na requires C.62.07%; H. 4.7l%.

EXAMPLE 33 i-( 2-Acetyl-3-hydroxyphenoxy)-2-Hydroxy-3-p- Cynnophenoxypropane.

A solution of 2.6-dihydroxyacetophenone (15.2 g). p-cyanophenyl-glycidyl ether l7.5 g) and benzyltrimethylammonium hydroxide l0 drops of a 40% solution) was heated under reflux for 2 days. The solvent was then removed by evaporation under reduced pressure to give l-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-pcyanophenoxy -propane. 28.4 g. as a beige solid. A portion was recrystallized from ethanol affording cream prisms m.p. l57-l58.

Analysis: Found: C. 65.95%; H. 5.l l%; N. 4.23%; C H NQ. requires C, 66.05%; H.5.24%; N. 4.28%.

EXAMPLE 34 l -(Z-Carbethoxychromon-51yloxy)-2-Hydroxy-3-p Cyanophenoxypropane.

A suspension of l-(2-acetyl-3-hydroxyphenoxy)-2- hydroxy-3-p-cyanophenoxypropane (l3.l g) in diethyl oxalate 15 ml) was added to a suspension of sodium ethoxide, prepared from sodium (3.0 g) and ethanol (30 ml) in dry benzene (200 ml). The resulting mixture was heated under reflux for 2 hours. cooled. poured onto ice lOO g). and acidified with a solution of acetic acid (l2 ml) in water ml). The benzene layer was separated, and the aqueous layer extracted with ether (3 X 25 ml). The extracts were combined with the organic layer. the solvent was removed. and the residue was dissolved in absolute ethanol lOO ml) to which hydrochloric acid (5 drops) was added. The yellow solution was heated under reflux for 1 hour and the solvent removed to give a yellow solid. Recrystallization from ethanol gave l-(Z-carbethoxyehromon-5-yloxy)-2- hydroxy-3-p-cyanophenoxypropane (5.4 g) as a beige solid mp. l37-l39C.

EXAMPLE 35 i-(2-Carboxychromon-5-yloxy )-2-Hydroxy- 3 p- Cyanophenoxypropane Sodium Salt.

A solution of sodium hydroxide (0.4 g) in ethanol (50 ml) was added to u solution of l-(2- carbcthoxychromon-S-yloxy)-2-hydroxy-3-p-cyanophenoxypropane (4.l g) in ethanol (100 ml). The resulting suspension was heated under reflux on a water bath for l hour. allowed to cool. and the precipitate filtercd off. washed with ethanol. and dried. it was then dissolved in water. the solution treated with charcoal. filtered. and freeze-dried to give the sodium salt (2.l g) as a pale beige solid. m.p. l80l85C.

Analysis: Found: C. 49.82%; H. 4.59%; N. 2.60% C 'H NO Na. 4H O requires C. 50.6%; H. 4.67%; N. 2.95%.

EXAMPLE 36 l-( 2-Acetyl-3-hydroxyphenoxy )-2-Hydroxy-3-p-Nitrophenoxypropane.

A solution of 2.o-dihydroxyaeetophenone (l5.2 "3) p-nltrophenyl-glycldyl ether l9.5 g) and henzyltrimethylammonium hydroxide l drops of a 40% solution) in 2 -ethoxyethanol (75 ml) was heated under reflux for 3 days. The solvent was removed under reduced pressure and the resulting beige solid triturated with ether. filtered oft and dried to give l(2-acetyl-3- hydroxyphenoxy)-2-hydroxy-3-nitrophenoxypropane (23.0 g). A portion was recrystallized from ethanol to give beige prisms m.p. l43l45.

Analysis: Found: C. 59.03%; H. 4.88%; N.4.00%; C H NO requires C. 58.79% H. 4.93%; N. 4.03%.

EXAMPLE 37 l-( Z-Carbethoxychromon-S-yloxy )-2-Hydroxy-3-p- Nitrophenoxypropane.

A solution of l-(2-acetyl-3-hydroxyphenoxy)-2- hydroxy-3-p-nitrophenoxypropane (20.82 g) in diethyl oxalate (22.5 ml) was added to a suspension of sodium ethoxide. prepared from sodium (4.5 g) and ethanol (45 ml). in dry ether (300 ml). The resulting yellow suspension was heated under reflux for 2.5 hours, then poured onto ice (l50 g) and acidified with a solution of acetic acid (24 ml) in water (l60 ml). The twophase mixture. after filtering to remove starting material (6.0 g) and washing with a litter ether. was separated. The aqueous layer was extracted with ether (4 X 50 ml). and the extracts added to the organic layer. The solvent was then removed and the residue dissolved in absolute ethanol I00 ml) to which hydrochloric acid (5 drops) was added. The solution was heated under reflux for l hour. and the solvent was then removed to give a brownish-yellow oily solid. This was triturated with ether to give l-(2-carbethoxy-chromon-5-yloxy-3- p-nitrophenoxypropane (12.0 g) as a yellow solid. A portion was recrystallized from ethanol to give yellow prisms m.p. l54-l56.

Analysis: Found: C. 58.56%; H. 4.43%; N. 3.23%; C H NO requires C. 58.74%; H. 4.46%; N. 3.26%.

EXAMPLE 38 l-( 2-Carboxychromon-S-yloxy )-2-Hydroxy-3-p Nitrophenoxypropane Sodium Salt.

A solution of sodium hydroxide (0.8 g) in ethanol (50 ml) was added to a suspension of l-(2- carbcthoxychromon-S-yloxy)-2-hydroxy-3-p-nitrophenoxypropane (8.58 g) in ethanol lOO ml) at room temperature. The mixture was heated under reflux for Analysis: Found: C. 49.93%; H. 3.64%; N3.06%; C H NO..Na. 2H,O requires C. 49.70%; H. 3.95%; N.

EXAMPLE 39 l-( 4-Acetyl-3-hydroxyphenoxy )-2-Hydroxy- 3- Phenoxypropane.

A solution of resacetophenone l5.2 g). phenylglyci dyl ether (l5.0 g) and benzyltrimethylammonium hydroxide (5 drops of a 40% solution in 2-ethoxyethanol ml) was heated under reflux for 2 days. Removal oi solvent under reduced pressure yielded a dark. Viscous oil. which was allowed to stand for 48 hours. by which time it has crystallized to a solid mass. This was triturated with aa mixture of ether and light petroleum (b.p. 40-60.). filtered. washed with a little more etherpetroleum and dried. Crystallization from methanol gave l-(4-acetyl-3-hydroxyphenoxy)-2-hydroxy-3- phenoxypropane as a greyish-white solid. 9.0 g. m.p. 63-65.

Analysis: Found: C. 67.2%; H. 6.0%; C. H...0,. requires C. 67.5%; H. 6.0%.

EXAMPLE 40 l-( 2-Carboxychromon-7-yloxy )-2-Hydroxy-3- Phenoxypropane.

A solution of l-(4-acetyl-3-hydroxyphenoxy)-2- hydroxy-3-phenoxy-propane (6.04 g) in diethyl oxalate 15 ml) was added to a suspension of sodium ethoxide. prepared from sodium (3.0 g) and ethanol (30 ml). in benzene (50ml). The mixture was heated under reflux for L5 hours, then cooled and filtered. The residual yellow sodium salt was washed with ether. dried. and dissolved in a mixture of glacial acetic acid ml) and concentrated hydrochloric acid (30 ml). This solution was heated under reflux for l hour. cooled, and poured with stirring into cold water (500 ml Theprecipitated solid (6.0 g) was filtered off and crystallized from methanol to give l-(2-carboxychromon-7-yloxy-3- phenoxypropane (4.3 g) as an off-white solid. m.p. 222-223.5.

Analysis: Found: C. 63.3%; H. 4.5% C..,H..,O requires C, 64.l%; H. 4.5%.

EXAMPLE 41 l-( 2-Carboxychromon-7-yloxy )-2-Hydroxy-3- Phenoxypropane Sodium Salt.

Sodium carbonate solution (0. l N; lOO ml) was added to l-(2-carboxy-chromon-7-yloxy)-2-hydroxy-3- phenoxypropane (3.563) and the mixture warmed on the water-bath until all the solid had dissolved. The solution was eharcoaled. filtered and freeze-dried to give the sodium salt (4.l g) as a white solid m.p. 235-240.

Analysis: Found: C. 57.29%; H. 4.34%; C .H. 0,Na. H,0 requires C. 57.58%; H. 4.33%.

EXAMPLE 42 l-( 2-Acetyl-3-hydroxyphenoxy )-2-Hydroxy-3-p- Carbethoxyphenoxypropane A solution of 2.6-dihydroxyacetophenone (15.2 g). 4-carbcthoxyphenylglyeidyl ether (22.2 g) and bcnzyltrimcthylammonlum hydroxide l0 drops oi n 40% solution) in 2-ethoxyethanol (75 ml) was heated under reflux for 48 hours. The solvent was then removed under reduced pressure. and the residual solid was triturated with ether to give a yellow powder (23.0 g). Re-

crystallization from aqueous ethanol yielded l-(2- Aeetyl-3-hydroxyphenoxy)-2-hydroxy-3-p carbethoxyphenoxypropane as pale yellow needles. mp. 104-l05.5C.

Analysis: Found: C. 64.26; H. 6.04% C H O requires C. 64.16; H. 5.92%.

EXAMPLE 43 l-( 2-Carbethoxychromon-S-yloxy )-2-Hydroxy-'.l-p- Carhethoxyphenoxypropane.

To a suspension of sodium ethoxlde. prepared from sodium (3.0 g) and ethanol (30 ml) in dry ether (200 ml). was added a solution of l-(2-acetyl-3- hydroxyphenoxy)-2-hydroxy-3-p-carhethoxyphenoxypropane 15.0 g) in diethyl oxalate 15 ml). The mixture was heated under reflux for 2 hours. and then poured onto ice 100 g). After acidification with a solution of acetic acid 12 ml) in water (80 ml). the ether layer was separated and the aqueous layer extracted with ether (3 X 25 ml). The combined ethereal extracts were evaporated under reduced pressure to give an orange oil. This was dissolved in ethanol (96%. 100 ml) containing hydrochloric acid drops) and the solution was heated under reflux for 1 hour. The ethanol was then removed under reduced pressure to yield a beige solid 18.65 g). Crystallization from ethanol gave l-(2- carbcthoxy-chromon-S-yloxy)-2-hydroxy-3-pcarbethoxyphenoxypropane as white prisms m.p. l33.5-l35C.

Analysis: Found: C. 63.37%; H. 5.17%; C- H O requires C. 63.15%; H. 5.30%.

EXAMPLE 44 l-( 2-Carboxychromon-5-yloxy )-2-Hydroxy-3-p- Carbethoxyphenoxypropane Sodium Salt.

A solution of sodium hydroxide (1.6 g) in ethanol (50 ml. 96%) was added to a solution of l-(2- carbethoxychromon-5-yloxy)-2 -hydroxy-3-pcarbethoxy phenoxypropane (9.13 g) in ethanol (100 ml. 96%). The suspension was heated under reflux for 2 hours and the ethanol was then removed under reduced pressure. The residue was dissolved in hot water. charcoaled. and the solution filtered and allowed to cool. l-(Z-Carboxychromon-S-yloxy)-2-hydroxy-3-pcarbethoxyphenoxypropane sodium salt (1.5 g) was precipitated as a white solid mp. 2l5-220.

Analysis: Found: C. 58.19%; H. 4.00%; C H O Na requires C. 58.7%; H. 4.2 70.

EXAMPLE 45 l-( 2-Acetyl-B-hydroxyphenoxy )-2-Hydroxy-3-( 2.5- dimethylphenoxy)propane A solution of 2.o-dihydroxyacetophenone (15.2 g). 2.5 -dimethylphenylglycidyl ether l 7.8 g) and benzyltrimethylammonium hydroxide drops of a 40% solution) in 2-ethoxycthanol (75 ml) was heated under reflux for 2 days. The solvent was then removed under reduced pressure to give a dark viscous oil which soon crystallized. The sticky solid was triturated with ether.

filtered. and washed with small portions of ether to give l-(2-acctyl-3-hydroxyphenoxy)-2-hydroxy-3-(2.5- dimethylphenoxy) propane (15.6 g) as a cream powder. m.p. l04-l05.5C.

Analysis: Found: C.68.72%; H. 6.51%. cud 22 5 requires C. 69.07%; H. 6.71%.

EXAMPI r 1.

l 2-Carbethoxychromm1-15- loxy )-2-Hydroxy-3-( 2.5- dimethylphcnoxy) propane.

To a suspension of sodium ethoxide. prepared from sodium (3.0 g) and ethanol (30 ml). in dry ether (200 ml). was added a solution of l-(2-acetyl-3- hvdroxyphenoxy )-2-hydroxy-3-( 2.5-dimethylphenoxy) propane (13.2 g) in diethyl oxalate 15 ml). The resultant solution was heated under reflux for 2 hours. and then poured onto ice 100 a). After acidification with a solution of acetic acid 12 ml) in water ml). the ether layer was separated. and the aqueous layer extracted with ether (3 X 25 ml). The combined ethereal extracts were evaporated under reduced pressure to give a yellow oil. This was dissolved in ethanol (96%. 100 ml) containing hydrochlorid acid (10 drops) and heated under reflux for l hour. Removal of the ethanol under reduced pressure gave 1-(2- earbethoxychromon-5-yloxy)-2-hydroxy-3-(2.5- dimethylphenoxy) propane as a yellow gum (15.2 g) which could not be crystallized.

EXAMPLE 47 l- 2-Carboxychromon-5-yloxy )-2-Hydroxy-3-( 2.5- dimethylphenoxy)propane Sodium Salt.

A solution of sodium hydroxide (1.2 g) in ethanol 96%. 50 ml) was added to a solution of 1-(2- carbcthoxychromon-S-yloxy)-2-hydroxy-3-(2.5- dimethylphenoxy) propane (l2.4 g) in ethanol (96%. 50 ml). The resulting suspension was warmed under reflux for 1 hour. cooled. and the precipitate filtered off. washed with a little ethanol. and dried. it was then dissolved in hot water and the solution was charcoaled. filtered and freeze-dried to give l-(2-carboxychromon- 5-yloxy)-2-hydroxy-3-(2.5-dimethylphenoxy) propane sodium salt (8.5 g) as a white solid mp. 228-230C.

Analysis: Found: C. 60.42%; H. 5.01%; C,..H, O Na. l/2H,O requires C. 60.71%; H. 4.85%.

EXAMPLE 48 l-( 2-Acetyl-3-hydroxyphenoxy )-2-Hydroxy-3-( 2-npropylphenoxy )propane.

A solution of 2.6-dihydroxyacetophenone (15.2 g) 2-n-propylphenylglycidyl ether (19.2 g) and benzyl' trimethylammonium hydroxide 10 drops of a 40% solution) in 2-ethoxyethanol (75 ml) was heated under reflux for 48 hours. The solvent was then removed under reduced pressure to give a dark oil which soon crystallized. The sticky residue was triturated with ether. filtered. and washed successively with small portions of ether to give l-(Z-acetyl-3-hydroxyphenoxy)- 2-hydroxy-3-( 2-n-propylphenoxy) propane (17.8 g) as a primrose powder m.p. -86.5C.

Analysis: Found: C. 69.41%; H. 6.82%; C- H- O requires C. 69.75%; H. 7.02%.

EXAMPLE 49 l-( 2-Carbethoxychromon-5-yloxy )-2-Hydroxy-3-( 2-npropylphenoxy) propane.

To a suspension of sodium ethoxide. prepared from sodium (3.0 g) and ethanol (30 ml) in dry ether (200 ml). was added a solution of l-(2-acctyl-3- hydroxyphenoxy )-2-hydroxy-3-( 2-n-propylphenoxy)propane 13.8 g) in diethyl oxalate (15 ml). The resulting solution was heated under reflux for 2 hours then cooled and poured onto ice (100 g). After acidication with a solution of acetic acid (12 ml) in water (80 ml), the ether layer was separated and the aqueous layer was extracted with'ether (3 X 25 ml). The combined organic extracts were evaporated under reduced pressure, then dissolved in a mixture of ethanol (100 ml) and hydrochloric acid drops). This solution was heated under reflux for 1 hour. Alter removal of solvent under reduced pressure, 1-(2- carbethoxychromon-S-yloxy )-2-hydroxy-3-( 2-npropylphenoxy)propaae 19.0 g) remained as a viscous yellow oil which could not solidified.

EXAMPLE 50 l-( Z-Carboxychromon-S-yloxy )-2 -Hydroxy-3-(2-n-propylphenoxy)propane Sodium Salt.

A solution of sodium hydroxide (1.2 g) in ethanol (96%, 50 ml) was added to a solution of l-(2- carbethoxychromon-S-yloxy)-2-hydroxy-3-(2-npropylphenoxy) propane (12.8 g) in ethanol (96%, 50 ml). Theresulting suspension was heated under reflux for 1 hour, cooled, the solid filtered off, washed with ethanol, and dried. it was then dissolved in hot water, and the solution charcoaled, filtered and freeze-dried to yield 1-(Z-carboxychromon-S-yloxy)-2-hydroxy-3- (2-n-propylphenoxy) propane sodium salt (8.3 g) as a white solid, mp. 226-228C.

Analysis: Found: C, 60.18%; H, 5.18%; C,- H,,O Na.H O requires C, 60.26%; H, 5.29%.

EXAMPLE S1 1-( 4-Acetyl-3-hydroxyphenoxy )-2-Hydroxy-3-p- Cyanophenoxypropane.

A solution of 2,4-dihydroxyacetophenone (15.2 g), p-cyano-phenylglycidyl ether (17.5 g) and benzyltrimethyl-ammonium hydroxide 10 drops of a 40% solution) 1n Z-ethoxyethanol (75 ml) was heated under reflux for 48 hours. The solvent was then removed under reduced pressure to give a beige solid. This was triturated with a little ether and filtered to give a pale beige powder, (28.6 g). Recrystallization from ethanol yielded 1-(4-acetyl-3-hydroxyphenoxy)-2-hydroxy-3- (p-cyanophenoxy) propane as white needles, m.p. 161.5-163C.

Analysis: Found: C, 66.22%; H, 5.16%; N, 4.14%; C ,,H,,NO,, requires C, 66.05%; H, 5.24%; N. 4.28%.

EXAMPLE 52 l-(2-Carbethoxychromon-7-yloxy)-2-Hydroxy-3-(pcynnophenoxy)propane.

To a suspension of sodium ethoxide, prepared from sodium (6.0 g) and ethanol (60 ml) in dry ether (400 ml) was added a solution of l-(4-acetyl-3- hydroxyphenoxy)-2-hydroxy-3-(p-cyanopheaoxy)propane (26.2 g) and diethel oxalate (30 ml) in dimethyl sulphoxlde (100 ml). After heating under reflux for 2 hours, the suspension was poured onto ice (200 g), acidified with a solution of acetic acid (24 ml in water (160 ml), and the ether layer separated. The aqueous layer was extracted with ether (3 X 50 ml) and the combined ethereal extracts were evaporated under reduced pressure. The residue was dissolved in ethanol (200 ml) containing concentrated hydrochloric acid drops) and the solution heated under reflux for 1 hour. Removal of the ethanol under reduced pressure gave a solid (24.6 g). On crystallization from ethanol l-( 2-carbethoxychromon-7-yloxy7-2-hydroxy-3-( pcyanophenoxy)propane was obtained as white crystals m.p. l172.

Analysis: Found; C, 64.75%; H, 4.80%; N, 3.46%; C H NO requires C, 64.54%, H, 4.68%; N, 3.42%.

EXAMPLE 53 l-( 2-Carboxychromon-7-yloxy)-2-Hydroxy-3-(pcyanophenoxy)propane Sodium Salt.

C,,,H NO-,Na.H,O requires C, 57.02%; H, 3.83%, N,

Example 54 1-( 3-Acetyl-4-hydroxyphenoxy )-2-Hydroxy-3-( 4- cyanophenoxy )propane.

A solution of 2,5-dihydroxyacetophenone (30.4 g), P-cyanophenylglycidyl ether (35.0 g) and benzyltrimethylammonium hydroxide 10 drops ofa 40% solution) in 2-cthoxyethanol ml) was heated under reflux for 72 hours. The solvent was then removed under reduced pressure to give a dark viscous oil which rapidly solidified. This solid was extracted with ether in a Soxhlet thimble and the ether then removed to give a yellow solid residue. This was triturated with a little ethanol, filtered off, washed with a little more ethanol and dried. Some further material was obtained by grinding the residue from the Soxhlet thimble and extracting it with boiling ether. Recrystallization from aqueous ethanol gave 1-( 3-acetyl-4-hydroxyphenoxy )-2-hydroxy-3-( pcyanophenoxy)propane as lemon-yellow needles mp.

l l8-l 20C.

Analysis: Found: C66.01%; H, 5.20%; N, 4.19%; C ,,H, NO requires C, 66.05%; H, 5.24%; N, 4.28%.

EXAMPLE 55 1-( Z-Carbethoxychromon-6-yloxy )-2-Hydroxy-3-( pcyanophenoxy )propane.

To a suspension of sodium ethoxide, prepared from sodium (6.0 g) and ethanol (60 ml) in dry ether (400 ml and dimethyl sulphoxide (50 ml), was added a suspension ol 1-( 3-acetyl-4-hydroxyphenoxy)-2 -hydroxy- 3-(p-cyanopheaoxy)propane (26.2 g) in diethyl oxalate (30 ml). The resulting suspension was heated under reflux for 2 hours, cooled, and poured onto icc (200 g). Afler acidification with a solution of acetic acid (24 ml) in water ml), the ether layer was separated, and the aqueous layer extracted with ether (3 X 50 ml The combined organic extracts were evapo rated under reduced pressure to give a yellow solid. This was dissolved in ethanol (200 ml) containing hydrochloric acid (20 drops) and the solution heated under reflux for 1 hour. After cooling, the beige solid (20.0 g) was filtered off. Recrystallization from aqueous dioxane gave l-(2-carbethoxychromon-6-yloxy)-2- hydroxy-3-(p-cyanophcnoxy) propane (17.3 g) as pale yellow crystals. m.p. 1501 52C. A portion was again crystallized from ethanol to give cream crystals n1.p. 151152.5C.

Analysis: Found: C. 64.34%; H. 4.52%; N. 3.31%; C H NO, requires C. 64.54%; H. 4.68%; N. 3.42%.

EXAMPLE 56 1-( ZCarboxyehromon-(iyloxy )Q-Hydroxy-li-t p-eyanophenoxy)propane Sodium Salt.

A solution oi" sodium hydroxide (1.6 g) in ethanol (50 ml) was added to a solution oi l-(2- earboxychromon e-yloxy)-2-hydroxy-3-(p-cyanophenoxy)propane 16.1 g) in ethanol (100 ml). The resulting suspension was heated under reflux for 1 hour. cooled. filtered. and the solid washed with a little ethanol and dried. it was then dissolved in water. the solution charcoaled. filtered and freeze-dried to give 1-(2- carboxychromon-6-yloxy)-2-hydroxy-3-(p-eyanophenoxy)propane sodium salt 16.5 g) as a pale yellow solid m.p. 2s5-290c.

Analysis: Found: C. 57.15%; H. 3.60%; N. 3.23%;

C .,H..NO,Na.H O requires C57.02%; H. 3.83%; N.

EXAMPLE 57 l-( 2-Acetyl-3-hydroxyphenoxy )-2-Hydroxy-3-( mtriliuoromethylphenoxy)propane.

A solution of 2.6-dihydroxyacetophenone (30.4 g). m-trifluoromethylphenylglycidyl ether (43.6 g) and benzyltrimethylammonium hydroxide (20 drops of a 40% solution) in 2-ethoxyethano1 (150 ml) was heated under reflux for 48 hours. The solvent was then removed by evaporation under reduced pressure to give a yellow residue. This was triturated with ether. filtered off and washed with ether to give a yellow solid (52.0 g). Crystallization from ethanol gave 1-(2-acety1-3- hydroxyphenoxy)-2-hydroxy-3-(m-trifluoromethylphenoxy)propane as cream needles mp. l112C.

Analysis: Found: C. 58.55%; H. 4.82%; F. 15.18%; C,..H.,F O requires C. 58.3%; H. 4.63%; F. 15.4%.

EXAMPLE 58 l-( 2-Carbethoxychromon-S-yloxy)-2-Hydroxy-3-( mtrifluoromcthylphenoxy)propane.

A suspension of 1-(2-accty1-3-hydroxyphenoxy)-2- hydroxy-3-(m-trifluoromethylphenoxy)propane (29.6 g) in diethyl oxalate (30 ml) was added to a suspension of sodium cthoxide. prepared from sodium (6.0 g) and ethanol (60 ml) in dry ether (400 ml). The resulting solution was heated under reflux for 2 hours. cooled. and poured onto ice (200 g). After acidification with a solution of acetic acid (24 ml) in water 160 ml). the ether layer was separated. and the aqueous layer extracted with ether (3 X 50 ml). The combined extracts were evaporated under reduced pressure. and the rcsiduedissolved in ethano1.(96%. 100 ml) to which hydrochloric acid drops) was added. This solution was heated under reflux for 1 hour. and the ethanol then removed under reduced pressure to give a beige solid. which was crystallized from aqueous ethanol to yield 1-( 2- carhcthoxychromon-S-yloxy)-2-hydroxy-3-( mtrilluoromethylphcnoxy)propane 19.5 g) as white needles mp 7075C.

Analysis: Found: C. 55.62%; H. 4.08%; F. 11.76%; C H...F O .H O requires C. 56.2%; H. 4.51%: F.

EXAMPLE 59 l-( Z-Carboxychromon-5-y1oxy )-2-Hydroxy-3-( mtrifluoromethylphenoxy)propane Sodium Salt.

A solution of sodium hydroxide (1.6 g) in ulhunol (96%. 50 ml) was added slowly with stirring to a hot solution of l-(2-carbethoxychromon-5-yloxy)-2- hydroxy-3-(in-triiluoromethylphenoxy)propnne 18.1 g) in ethanol (96%. ml The resulting mixture was heated under reflux for 1 hour. cooled. and the prec1p1- tated solid filtered ofl. washed with ethanol and dried.-

It was then crystallized from water to give 1-(2- carboxychromon-S-yloxy )-2-hydroxy-3-( mtrifluoromethylphenoxy)propane sodium salt 14.25 g) as shiny white flakes. m.p. 235-237C.

Analysis: Found: C. 49.90%; H. 3.66%; F. 12.41%; C .,H,.F;,O Na.2H-;O requires C. 49.80%; H. 3.76%; F. 1 1.82%.

EXAMPLE 60 l-( 2-Acetyl-3-hydroxyphenoxy )-2-Hydroxy-3-( 2.4- dichlorophenoxy )propane.

A solution of 2.6-dihydroxyacetophenone (30.4 g). 2.4-dichloropheny1glycidyl ether (43.8 g). and benzyltrimethylammonium hydroxide (20 drops of 40% solution) in 2-ethoxyethano1 ml) was heated under reflux for 60 hours. The solvent was then removed under reduced pressure to give a yellow oil. This was triturated with ether to give a solid which was filtered. washed with ether. dried. and crystallized from ethanol to yield 1-(2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3- (2.4-dichlorophenoxy)propane (36.1 g) as yellow needles. m.p. 130-132C.

Analysis: Found: C. 54.84%; H. 4.32%; C1. 19.04%; C. H...Cl,O,. requires C. 55.1%; H. 4.35%; Cl. 19.11%.

EXAMPLE 61 l-( 2-Carbethoxychromon-5-yloxy )-2-Hydroxy-3-( 2.4- dichlorophenoxy )propane.

A suspension of l-(2-acety1-3-hydroxyphenoxy)-2- hydroxy-3-(2.4-dichlorophenoxy)propane (29.6 g) in dlethyl oxalate (30 ml) was added to a suspension of sodium ethoxide. prepared from sodium (6.0 g) and ethanol (60 ml) in dry ether (400 ml). The resulting mixture was heated under reflux for 2 hours. cooled. and then poured onto ice (200 g). After acidifying with a solution of acetic acid (24 ml) in water ml) the ethereal layer was separated. The aqueous layer was extracted with ether (3 X 50 m1) and the combined extracts evaporated to give a red oil. This was dissolved in ethanol (96%. 100 ml) containing hydrochloric acid 10 drops) and the solution heated under reflux for 1 hour. The solvent was then removed under reduced pressure to give a red oil which was solidified by trimrating with ether. This solid was crystallized from ethanol to yield l-(2-earbcthoxychromon5-yloxy)-2- hydroxy-3-(2.4-dichlorophenoxy)propane (30.5 g) as cream crystals m.p. MP-100C.

Anulvsls: Found: C. 55.1891. H. 4.23%; Cl. 15.24%; C- H CI O requires C. 55.6%; H. 4.01%; C115.64%.

EXAMPLE 62 l-(Z-Carboxychromon-S-yloxy)-2Hydroxy-3-(2.4- dichlorophenoxy)propane Sodium Salt.

A solution of sodium hydroxide (1.6 g) in ethanol (50 ml) was added with stirring to a hot solution'of l- (2-carbethoxyehromon-5-yloxy)2-hydroxy-3-(2.4 dichlorophenoxy)propane (18.12 g) in ethanol (96%. 100 ml The resulting suspension was heated under reflux for 1 hour. then cooled and the precipitate filtered off. washed with ethanol. and dried. it was then dissolved in hot water. the solution charcoaled. filtered and allowed to cool. The precipitate was filtered off and dried. yielding 1-(2-carboxychromon-5-yloxy)-2- hydroxy-2-(2.4-dichlorophenoxy)propane sodium salt (11.9 g) as a grey-white solid, mp. 23l-233C.

Analysis: Found: C. 47.47%; H. 3.37%; Cl. 14.23%; C H. Cl,O-,Na.2H-..O requires C. 47.22%; H. 3.55%; C1. 14.67%.

EXAMPLE 63 l-( 2Acetyl-3-hydroxyphenoxy )-2-Hydroxy-3-( pfluorophenoxy)propane.

A solution of 2.6-dihydroxyacetophenone (30.4 g) p-fluorophenylglycidyl ether (33.6 g), and benzyltrimethylammonium hydroxide (lml of a 40% solution) in 2ethoxyethanol (150 ml) was heated under reflux for 48 hours. After removal of solvent under reduced pressure. the residual viscous oil was triturated with ether. filtered off. and washed with ether to give a yellow powder. Crystallization from aqueous ethanol gave 1- (2-acetyl-3-hydroxyphenoxy)-2-hydroxy-3-(p-fluorophenoxy)propane (39.2 g) as cream needles m.p. lll-'ll3C.

Analysis: Found: C. 63.68%; H. 5.48%; F. 5.89%; C,,H.-,FO,-. requires C. 63.74%; H. 5.35%; F. 5.93%.

EXAMPLE 64 1-( 2-Carbethoxychromon-S-yloxy)-2-Hydroxy-3-(pfluorophenoxy)propane.

A suspension of 1-(2-acetyl-3-hydroxyphenoxy)-2- hydroxy-3-(p-fluorophenoxy)propane (25.6 g) in diethyl oxalate (30 ml) was added to a suspension of sodium ethoxide. prepared from sodium (6.0 g) and ethanol (60 ml) in dry ether (400 ml). The mixture was then heated under reflux for 2 hours. cooled. and poured onto ice (200 g). After acidification with a solution of acetic acid (24 ml) in water (160 ml). the etheral layer was separated. and the aqueous layer was extracted with ether (3 X ml). The organicextracts were combined and concentrated under reduced pressure to give yellow oil. This was dissolved in ethanol (100 ml) containing hydrochloric acid (10 drops) and the solution heated under reflux for 1 hour. After removal of the solvent under reduced pressure the yellow residue was crystallized from ethanol to give 1-(2- carbethoxy-phenoxy)-2-hydroxy-3-(p-fluorophenoxy)- propane (22.0 g) as cream crystals. m.p. ll2-l 14C.

Analysis: Found: C. 62.61%; H. 4.89%; F. 4.80% C H FO, requires C. 62.68%; H. 4.76%. F. 4.72%.

EXAMPLE 65 30 lution of l-( Z-carbethoxychromon-S-yloxy 2- hyd roxy-3-(p-fluorophenoxy)propane 16.08 g) in eth- .anol (96%. 100 ml). The resulting suspension was C H FO Na.l/2H,O requires C, 56.30%; H. 3.73%; F.

EXAMPLE 66 l-(2-Acety1-3-hydroxyphenoxy)-2-Hydroxy-3-(4- Cyano-3-methoxyphenoxy)propane.

A solution of 2.6-dihydroxyacetophenone (7.6 g). 4-eyano-3-methoxyphenylglycidyl ether (10.25 g) and benzyltrimethylammonium hydroxide (5 drops of a 40% solution) in 2-ethoxyethanol (37.5 ml) was heated under reflux for 48 hrs. After removal of the solvent under reduced pressure. a beige solid remained. This was triturated with ether, filtered. and washed with a mixture of ethanol and ether to yield l-(2-acetyl-3- hydroxyphenoxy(-2-hydroxy-3-(4-cyano-3-methoxyphenoxy)propane (12.15 g) as a primrose solid. mp. 155-l57.

EXAMPLE 67 1-(Z-Carbethoxychromon-S-yloxy)-2-Hydroxy-3-(4- Cyano-3-methoxyphenoxy )propane A suspension of l-(Z-acetyl-3-hydroxyphenoxy)-2- hydroxy-3-(4-cyano-3-methoxyphenoxy)propane (11.9 g) in diethyl oxalate (12.4 ml) was added to a suspension of sodium ethoxide. prepared from sodium (2.3 g) and ethanol (25 ml). in dry ether (200 ml). Dimethyl sulphoxide 100 ml) was then added to dissolve the solid. and the solution was heated under reflux for 2.5 hours. then cooled and poured onto ice (100 g). After acidification with a solution of acetic acid (12 ml) in water ml). the ether layer was separated and the aqueous layer was extracted with ether (4 X 150 ml). The solvent was then removed from the combined organic layers under reduced pressure. and the residue was dissolved in ethanol ml) to which hydrochloric acid .(1 ml) was added. The solution was heated under reflux for 1 hour. then cooled and the solvent re moved to give a yellow gum. Trituration with an etherethanol mixture gave a yellow solid (10.2 g). This was recrystallized twice from ethanol to give l-(2- carbethoxychromon-S-yloxy)-2-hydroxy-3-(4-cyano-3- methoxyphenoxy)propane (4.3 g) as an off-white solid. mp. 143-145.

EXAMPLE 68 l-(2-Carboxychromon-5-yloxy)-2-Hydroxy-3-( 4- Cyano-3-methoxyphenoxy)propane Soduim Salt.

A solution of sodium hydroxide (0.4 g) in ethanol (25 ml) was added slowly to a hot suspension of l-(2- carbethoxychromon-S-yloxy)-2-hydroxy-3-(4-eyano-3- methoxyphenoxy)propane (4.3 g) in ethanol (50 ml). The mixture was then heated under reflux for 1 hour. The resulting suspension was filtered hot. and washed with a little hot ethanol and dried. The residue was dissolved in water. and the solution charcoaled. filtered. and freeze-dried. Washing the product again with hot 31 ethanol gave l 2-carboxychromon-5-yloxy )-2- hydroxy-3-(4-cyano-3-methoxyphcnoxy)propane sodium salt (3.0 g) as a white solid. mp. 25926l.

EXAMPLE 69 Antiallergic Activity of Representative Compounds Compounds representative of the above examples were evaluated for antiallergic activity in the rat by the passive cutaneous anaphylaxis test (hereafter PCA). utilizing egg albumin as the antigen.

PCA is an experimentally induced allergic reaction which develops in the skin of test animals after intrave- Meun Reaction Dunneters In Militia-tors nous injection of an antigen. The intensity of such PCA reactions is assessed by measuring the diameters of wheals which develop in the skin of the test animal. Details of the PCA test can be found in the following references: l. Motar. Life Sciences. H465 (i963); and B. Ogilvie. immunology, l2.l i3 (1967).

in the following table, ID is the dose which reduced the diameter of the wheal by 50% when injected intravenously together with the antigen. At least 3 groups of 5 rats were used to determine the [D for each compound tested. The reference compound utilized was disodium chromoglycate (DSCG). The test compounds are identified by their respective Example Numbers above.

Test Compound by ID (p. moles/kg) Example Number Duration of Antiallergic Activity The duration of antiallergie activity of compounds lisnmple Number Allcr 25 p. mics/kg Allur 25 p "mics/k 0| IL-st (mnpnuml 0| DSCG 4 1.1.0103 lit-t :01 x (1.4 10.4 |0,n 0.7 ll 21420.4 l0 n:0.7 l5 ll ll:0.5 l0.n10.7 l I 10120.2 0.? 0. 5 810:0,7 H.010): 3K ll.2 20.3 9.7 :(H 10.4 xx :0} 57 8.4 :05 x1 10. a2 1.3 10.5 Hi :0} a5 ll: :02 [2.3 :0.2

EXAMPLE 71 Acute Toxicity Tests 30 Acute toxicity of compounds representative of the above Examples was determined in rats. The test compounds were administered intravenously in either 40 ml/kg of physiological saline or l0 mg/kg of propylene and saline. Compounds which are insoluble in saline were administered in i0 mg/kg of propylene and saline. Animals were observed for 1 week after administration of the compounds indicated in the following table. Doses administered represent the maximum dose possible and are limited by solubility factors. lD in the table is used as defined in Example 66. Test compounds are identified by their respective Example Number. above.

Test Compound by DOSE Therapeutic Ratio wherein:

R is selected from the group consisting of hydrogen.

alkyl of l to 4 carbon atoms, and a nontoxic pharmaceutically acceptable cation;

each of R, R. R", and R is hydrogen; and,

2. A compound as in claim I having the formula:

a o c R 3. A compound as in claim 1 having the formula:

0-CH2-CH(OH)-CH.,-

6 2 l l R R 4. A compound as in claim 1 having the formula:

carbethoxychromon-5-yloxy)-2-hydroxy-3-(p-cyanophcnoxy )-propane.

6. A compound as in claim I: l-(2-carboxychromon- 5-yloxy)-2-hydroxy-3-(p-cyanophenoxy)propane sodium salt.

7. A compound as in claim I: l-(2- carbethoxychromon-7-yloxy)-2-hydroxy-3-(pcyanophcnoxy) propane 8. A compound as in claim I: l-(2-carboxychromon- 7-yloxy)-2-hydroxy-3-(p-cyanophenoxy)propane sodium salt.

9. A compound as in claim I: l-(2- carbethoxychromon-6-yloxy)-2-hydroxy-3-(pcyanophenoxy) propane.

[0. A compound as in claim I: l-(2- carboxychromon-6-yloxy )-2-hydroxy-3-( p-cyanophcnoxy)propane sodium salt.

l t t l t 

1. A COMPOUND HAVING THE FORMULA
 2. A compound as in claim 1 having the formula:
 3. A compound as in claim 1 having the formula:
 4. A compound as in claim 1 having the formula:
 5. A compound as in claim 1: 1-(2-carbethoxychromon-5-yloxy)-2-hydroxy-3-(p-cyanophenoxy)-propane.
 6. A compound as in claim 1: 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-(p-cyanophenoxy)propane sodium salt.
 7. A compound as in claim 1: 1-(2-carbethoxychromon-7-yloxy)-2-hydroxy-3-(p-cyanophenoxy) propane.
 8. A compound as in claim 1: 1-(2-carboxychromon-7-yloxy)-2-hydroxy-3-(p-cyanophenoxy)propane sodium salt.
 9. A compound as in claim 1: 1-(2-carbethoxychromon-6-yloxy)-2-hydroxy-3-(p-cyanophenoxy) propane.
 10. A compound as in claim 1: 1-(2-carboxychromon-6-yloxy)-2-hydroxy-3-(p-cyanophenoxy)propane sodium salt. 